Certain n-anilino-ethyl - 2,2,6,6-tetramethyl - 1,2,3,6-tetrahydro pyridines and derivatives thereof

ABSTRACT

THE DISCLOSURE IS OF THERAPEUTICALLY USEFUL DERIVATIVES OF ARYLAMINOETHANE AND OF A PROCESS OF PRODUCING THEM. THE COMPOUNDS HAVE THE FORMULA:   R1-N(-X)-(CH2)2-N&lt;(-C(-CH3)2-Z-CH2-C(-CH3)2-)   WHEREIN:   Z REPRESENTS THE GROUP -CH2-CH2- OR THE GROUP -CH=CH-, R1 IS A SUBSTITUTED OR UNSUBSTITUTED PHENYL, BENZYL OR PHENETHYL RADICAL OR AN A-NAPHTHYL OR FURFURYL RADICAL, X IS A HYDROGEN ATOM, CH3 OR A RADICAL COR, WHICH LATTER CAN BE COOC2H5, A SATURATED OR UNSATURATED ALIPHATIC ACID RESIDUE WITH A STRAIGHT OR BRANCHED CHAIN CONTAINING 1 TO 6 CARBON ATOMS, A SATURATED OR UNSATURATED ARYL-ALIPHATIC ACID RESIDUE WITH A STRAIGHT OR BRANCHED ALIPHATIC ACID CHAIN CONTAINING 1 TO 4 CARBON ATOMS, A SUBSTITUTED OR UNSUBSTITUTED AROMATIC ACID RESIDUE OR A PHENOXYACETIC ACID RESIDUE WHICH MAY BE SUBSTITUTED IN ITS BENZENE RING. THE METHOD COMPRISES REACTING A COMPOUND OF THE FORMULA:   HCL CL-(CH2)2-N&lt;(-C(-CH3)2-Z-CH2-C(-CH3)2-)   WITH AN AMINE SUCH AS H2NR OR   R-NH-X

United States Patent 3,573,319 CERTAIN N-ANILINO-ETHYL 2,2,6,6-TETRA- METHYL 1,2,3,6-TETRAHYDRO PYRIDINES AND DERIVATIVES THEREQF Andrea Pedrazzoli and Gianmario Cipeiietti, Milan, Italy, assignors to Socit dEtudes de Recherches et dApplicatious Scientifiques et Medicales E.R.A.S.M.E., Paris, France No Drawing. Filed Aug. 21, 1967, Ser. No. 661,810 Claims priority, application Great Britain, Aug. 23, 1966, 37,825/66; Nov. 21, 1966, 52,072/66 Int. Cl. C0711 31/42 US. Cl. 260-296 4 Claims ABSTRACT OF THE DISCLOSURE The disclosure is of therapeutically useful derivatives of arylaminoethane and of a process of producing them. The compounds have the formula:

CH3 CH3 wherein Z represents the group -CH CH or the group --CH=CH-,

R is a substituted or unsubstituted phenyl, benzyl or phenethyl radical or an a-naphthyl or furfuryl radical,

X is a hydrogen atom, CH or a radical COR, which latter can be COOC H a saturated or unsaturated aliphatic acid residue with a straight or branched chain containing 1 to 6 carbon atoms, a saturated or unsaturated aryl-aliphatic acid residue with a straight or branched aliphatic chain containing 1 to 4 carbon atoms, a substituted or unsubstituted aromatic acid residue or a phenoxyacetic acid residue which may be substituted in its benzene ring. The method comprises reacting a compound of the formula:

CH3 0N NOHzCH2-Cl(HCl) III CE Ia CHa with an amine such as H NR or The present invention concerns new derivatives of arylaminoethane which are therapeutically useful and also their process of preparation.

The compounds of the invention have the following general formula:

C H3 0 H3 wherein:

Z represents the group CH CH or the group CH=CH-,

R is a substituted or unsubstituted phenyl, benzyl or phenethyl radical or an a-naphthyl or furfuryl radical,

Patented Mar. 30, 1971 ice X is a hydrogen atom, CH or a radical COR, which latter can be COOC H a saturated or unsaturated aliphatic acid residue with a straight or branched chain containing 1 to 6 carbon atoms, a saturated or unsaturated aryl-aliphatic acid residue with a straight or branched aliphatic chain containing 1 to 4 carbon atoms, a substituted or unsubstituted aromatic acid residue or a phenoxyacetic acid residue which may be substituted in its benzene ring.

The invention also relates to salts of these acids with inorganic acids which are therapeutically usable.

The products of the invention can be prepared by a process indicated as follows:

(III) Where Z, X and R have the meanings indicated above. When in Formula III above X is H, the NH group so obtained can be reacted with an acid chloride:

CH3 CH3 COR I L NOH2OH2NR1 I H CH3 CH3 COR having the meaning already given.

For instance, 1-( i3 chloroethyl) 2,2,6,6 tetramethylpiperidine hydrochloride can be reacted with an amine in an inert organic solvent under reflux conditions, in the presence of an inorganic hydrogen acceptor and catalytic amounts of Cu for 3 to 48 hours. At the end of the reaction, the material is washed with a caustic soda solution, the organic phase is separated, concentrated and distilled under vacuum. The product can be used as such or, as previously indicated when the amine in R NH can be reacted with an acid chloride RCOCl in an inert organic solvent in the presence of a basic hydrogen acceptor (such as the tertiary amines) to give the corresponding amides.

l-(B-chloroethyl) 1,2,3,6 tetrahydro 2,2,6,6 tetramethyl-pyridine hydrochloride can be reacted in similar manner with an amine:

in an inert organic solvent under reflux conditions, in the presence of an inorganic H acceptor and catalytic amounts of Cu for 3 to 48 hours. At the end of the reaction, the reacted mass is washed with an alkaline solution, the organic phase is separated, and the product obtained is concentrated and distilled under vacuum.

The products of the invention are stable to light and to heat. They have a low toxicity and a remarkable pharmacological activity.

The most interesting materials administered in doses greater than pharmacologically active ones and always orally to albino rats over several days showed no negative element; there was no modification of the weight increase graph, with respect to control animals, in the hematic formula and in the constant hemochromocitometric principles, no variation in hepatic activity and metabolism and the gastric tolerability is satisfactory.

The most interesting compounds of the invention from The compounds of the invention in general clearly affeet sedation caused by barbiturates in mice, but only at elevated doses.

Several compounds of the invention have in vitro a clear inhibiting action on contraction of the isolated guineapig intestine, determined by barium chloride or by acetylcholine.

In Table I the most important properties of various compounds are tabulated (13, 14, 16, 21 the formulae of the pharmacological standpoint, when administered to which are given in Table II).

TABLE I Analgesic activity in mice Electr. stimula- Sedative/tranquillising activity Inhib. excitation Rota-Rod acute tion tail Phenyl-p-quinone Hot plate amphetamine toxicity Compound DL p.o., Dose, Protcct., Dose, Protect., Dose, Penman. Dose, Protect, Dose, Percent an- No. rug/kg. mg./kg. percent mg/kg. percent rug/kg. 1ncr. rug/kg. percent mg./kg. nnals died 2 13 1, 200 g 50 50 100 2. 2 300 0 so 50 14 3, 000 55 50 80 2. 9 150 50 200 50 16 2, 000 25 150 45 200 2. 12 400 50 200 50 21 3, 000 25 52 250 50 100 2. 13 7O 50 100 1 Increase in time of permanence on the plate. I 2 Percent animals which died before the standard time.

anaesthetised cats (Nembutal) in doses higher than pharunacologically active ones showed no effect on the shape of the graph of pressure and respiration nor on the ECG trace.

They have a general analgesic action evaluted by the following tests:

The compounds of the invention have been studied also from the tranquilising activity/ sedative standpoint, by the following tests:

(a) rota-rod (rotating rod), (De Wied, D., Jenkins,

R., Proc. Soc. Exptl. Biol. Med, 1958, 99, 44);

(b) motive excitation caused by amphetamine, (Dunham, N. W., Muja, T. S., J. Amer. Pharm. Assoc., 1957, 46, 208).

Several compounds of the invention have an activity of this type.

Also, several other compounds have a convulsivant action; this property has been studied by the methods:

(a) of shock due to cardiazol'e (Riley, H., Spinks, A., J.

Pharm. a. PharmacoL, 1958, 10, 657 and 721);

(b) of shock due to strychime (Riley, H., Spinks, A.,

ibid);

(c) electro-shock (T oman, J. E. P., Everett, G. M., Psychopharmacology-Cassel, London, 1958).

The compounds of the invention have been subjected to tests for anti-inflammatory activity, according to the test for experimental oedema of the rat paw, caused by:

(a) carragenine (Winter, C. A., Proc. Soc. Exptl. Biol.

Med, 1962, 111, 544);

(b) kaolin (Coubon R., Arch. Int. Pharmacodyn, 1954,

and sometimes also by:

(c) serotonine (Stone, C. A., J. Pharmacol. Exptl.

Therap., 1961, 131, 73).

Several showed no antipyretic activity (or only very weak activity) by the test for experimental hyperpyrexia in rabbits caused by intravenous injection of polyvalent vaccine.

The following examples illustrate the invention without limitation:

EXAMPLE 1 N[2-(2",2",6",6"-tetramethyl-piperid-1"-yl)- ethyl]-2,3-dimethylaniline A mixture of 21.2 g. of 2,3-dimethylaniline, 24 g. of

2-(2',2',6,6-tetramethyl-piperid 1 y1)-ethyl chloride hydrochloride, 27.6 g. of anhydrous potassium carbonate, 1 g. of copper powder and ml. of anhydrous toluene were heated under reflux for 24 hours. After cooling, the solution was washed with 10% caustic soda solution and then with Water. The dried organic phase was concentrated and distilled under vacuum to give 21 g. of an oil boiling at to 160 C. at 0.1 mm. Hg. It was allowed to stand; a solid product of M.P. 3941 C. was obtained.

This base, when dissolved in isopropanol and treated with an isopropanol solution of hydrochloric acid, gives the hydrochloride which after crystallisation from methanol has an M.P. of 238-240 C.

EXAMPLE 2 N-methyl-N- [2- 2",2' ',6",6"-tetramethyl-piperid- 1"-yl) -ethyl] -3-chloroaniline A mixture of 28.5 g. N-methyl-m-chloro-aniline, 24 g. 2-(2',2,6',6'-tetramethyl-piperid 1' y1)-chloride ethyl hydrochloride, 27.64 g. of anhydrou potassium carbonate, 1 g. of copper powder and 150 ml. of anhydrous toluene was heated under reflux for 24 hours. The mixture was cooled, filtered, washed with 10% NaOH and then with water. The dried organic phase was concentrated under vacuum and distilled to give 23.7 g. of an oil boiling at -185 C. at 0.2 mm. Hg. This base, when dissolved in isopropanol and treated with hydrogen chloride gas, gives a hydrochloride having an M.P. of 160- 163 C. after recrystallisation from isopropanol.

EXAMPLE 3 N-carbethoxy-N-[2'-(2",2",6",6"-tetramethyl-piperid- 1"-yl -ethyl] -2,3-dimethylaniline 14.4 g. of N-2-(2",2",6",6"-tetramethyl-piperid-1"- yl)-ethyl-2,B-dimethylaniline, 5.45 g. of ethyl chloroformate and 100 ml. of anhydrous benzene were heated under reflux for 8 hours. The mixture was cooled and treated with a dilute solution of NaOH and then with Water. The dried organic phase was concentrated under vacuum and the residue was crystallized from hexane to give 12 g. of pure product; M.P. 75 78 C.

EXAMPLE 4 N-propionyl-N-[2-(2",2",6",6-tetramethyl-piperid- 1"-yl) -ethyl] -3 -chloro-aniline 14.75 g. of N-2'-(2",2",6",6"-tetramethyl-piperid-1"- yl)-ethyl 3 chloro-aniline, 4.7 g. of propionyl chloride and 100 ml. of anhydrous benzene were heated under reflux for 6 hours. The cooled solution was treated with an aqueous solution of sodium hydroxide and then with water. The dried organic extracts were concentrated under vacuum and the residual oil was crystallised from isopropyl ether to give 13 g. of pure product; M.P. 118- 120 C.

EXAMPLE 5 N-(p-chloro-phenoxyacetyl)-N-[2-(2,2,6,6"- tetramethylpiperid-1"-yl) -ethyl] -2,3-dimethylaniline 14.4 g. of N-2-(2,2",6",6-tetramethylpiperid-l"- yl)-ethyl-2,3-dimethyl-aniline and 10.25 g. of p-chlorophenoxyacetylchloride in 100 ml. of anhydrous benzene were heated under reflux for 8 hours. After cooling, the solid obtained was filtered and crystallised from isopropanol to give 20 g. of pure hydrochloride; M.P. 207- 209 C.

EXAMPLE 6 N [2' (1",2,3",6"-tetrahydro 2",2",6",6"-tetramethyl-pyridyl 1") ethyl] 3 (trifluoromethyl)- aniline fi-(l,2,3,6-tetrahydro 2,2,6,6 tetramethyl-pyridyl-l)- ethyl chloride hydrochloride (M.P. 222-224 C.), prepared as the starting material for the synthesis of the product of the invention, was prepared by reacting l-(flhydroxyethyl) 1,2,3,6 tetrahydro 2,2,6,6 tetramethyL,

pyridine (M.P. 72-74 C.) with thionyl chloride under reflux in benzene solution and crystallizing from ethanol the product obtained.

A mixture of 32 g. of m-trifiuoromethyl-aniline, 23.8 g. of B-(1,2,3,6-tetrahydro 2,2,6,6 tetramethy1-pyridyl)- ethyl chloride hydrochloride, 27.6 g. of anhydrous potassium carbonate, 2 g. of Cu powder and 200 ml. of anhydrous toluene was heated under reflux for 24 hours; after cooling, the solution was washed with 10% sodium hydroxide, then with water; the dried organic phase was concentrated and distilled under vacuum to give a yield of 19 g. of an oil boiling at 175-180 C. under 0.8

mm. Hg; after several hours, a solid product was obtained having a melting point of 5860 C.

This base, when dissolved in acetone and treated with a hydrochloric acid solution in ethyl ether, gave a chloride which, after crystallization from isopropanol and drying under heat and vacuum, gave a melting point of 183- 186 C.

EXAMPLE 7 24 g. of a-phenethylarnine, 23.8 g. of B-(1,2,3,6-tetrahydro-2,2,6,6-tetramethyl-pyridyl-1)-ethyl chloride hydrochloride, 27.6 g. of anhydrous potassium carbonate, 3 g. of Cu powder and 200 ml. of anhydrous toluene were refluxed together for 44 hours; after cooling, the solution was washed with 10% sodium hydroxide solution and then with Water; the dried organic phase was concentrated and distilled under vacuum to give 19.6 g. of an oil boiling at 149-l52 C. under 1 mm. Hg.

The phase dissolved in isopropanol and treated with an ethereal solution of hydrochloric acid gave the hydrochloride, which after crystallization from ethanol gave an M.P.=226 -227 C. (with decomposition).

EXAMPLE 8 19.4 g. of furfurylamine, 23.8 g. of B-(l,2,3,6-tetrahydro-2,2,6,6-tetramethyl-pyridyl 1) ethyl chloride hydrochloride, 27.6 g. of anhydrous potassium carbonate, 2 g. of Cu powder and 200 ml. of anhydrous toluene were refluxed together for 30 hours; after cooling, the solution was washed with 10% sodium hydroxide and then with Water; the dried organic phase was concentrated and distilled under vacuum to give 21 g. of an oil boiling at -139 C. under 0.5 mm. Hg.

The base, dissolved in isopropanol and treated with hydrochloric acid in isopropanol, gave a dichloride which after crystallization from ethanol, gave a melting point of 212-213 C. (with decomposition).

Various other compounds according to the invention have been prepared; the principal results are given in Table 1.

The principal compounds so made are tabulated in Table II. 

